Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Alpha adrenergic receptors are plasma membrane receptors which are located in the peripheral and central nervous systems throughout the body. They are members of a diverse family of structurally related receptors which contain seven putative helical domains and transduce signals by coupling to guanine nucleotide binding proteins (G-proteins). These receptors are important for controlling many physiological functions and, thus, have been important targets for drug development during the past 40 years. Examples of alpha adrenergic drugs include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma). However, most of these drugs produce undesirable side effects, possibly due to their interactions with other receptor subtypes. For example, clonidine is a well known centrally acting antihypertensive agent. However, it also produces untoward side effects such as analgesia, sedation, bradycardia and dry mouth which may be due to its lack of selectivity at xcex12 receptors.
xcex1-Adrenergic receptors were originally proposed to have only two (alpha and beta) subtypes (Berthelsen, S.; Pettinger W. Life Sci., 21, 595 (1977)). However, modern molecular biological and pharmacological techniques have led to the identification of at least 6 subtypes (xcex11a, xcex11b, xcex11c, xcex12a, xcex12b and xcex12c) of the adrenergic receptors (Bylund, D. B., Trends Pharmacol. Sci., 9, 356 (1988)).
Among many other therapeutic indications, xcex12 receptors are believed to modulate pain and behavioral depression by regulating locus coeruleus firing. In addition, xcex12 receptors are well known to be involved in effects on blood pressure, heart rate, vasoconstriction and on glaucoma. However, it is not known which therapeutic indications are controlled by each of these subtypes.
The effects of xcex12 receptor agonists on analgesia, anesthesia and sedation have been well documented for past 10 years (Pertovaara, A., Progress in Neurobiology, 40, 691 (1993)). For example, systematic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing antinociception. Another xcex12 agonist, medetomidine, which has better xcex12/xcex11 selectivity and is more potent at xcex12 receptors than clonidine, has been extensively studied for its antinociception effect. In the spinally-initiated heat-induced tail flick test in rats, systemic administration of medetomidine produced a dose-dependent antinociception which could be totally reversed by xcex12 receptor antagonists, atipamazole or idazoxan. Experimental studies of medetomidine on pain sensitivity in humans also indicated that this agent is very effective for ischemic pain, even though effective drug doses were high enough to produce sedation and considerable decreases in blood pressure.
Effects of xcex12 receptor agonists in anaesthetic practice have also been investigated (Bloor, B. C.; Flacke, W. E., Anesth. Analg., 61, 741 (1982)). The sedative effect of xcex12 agonists is regarded as good component of premedication. Another beneficial effect of xcex12 agonists in anaesthetic practice is their ability to potentiate the anaesthetic action of other agents and to reduce anaesthetic requirements of other drugs during surgery. Studies shows that premedication with 5 xcexcg kgxe2x88x921 of oral clonidine administration reduced fentanyl requirements for induction and intubation by 45% in patients undergoing aortocoronary bypass surgery (Ghingnone, M., et al., Anesthesiology, 64, 36 (1986)).
This invention is directed to novel indole and benzothiazole compounds which are selective for cloned human xcex12 adrenergic receptors. This invention is also related to uses of these compounds for any indication where use of an xcex12 adrenergic receptor agonist may be appropriate. Specifically, this includes use as analgesic, sedative and anaesthetic agents. In addition, this invention includes using such compounds for lowering intraocular pressure, treating migraine headache, hypertension, presbyopia, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemia, spasticity, diarrhea, nasal decongestion, urinary incontinence as well as for use as cognition enhancers and ocular vasoconstriction agents. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
The present invention is directed to compounds having the structure: 
where each of R1, R2 and R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C1-C7 alkenyl or alkynyl;
where each of R4, R5 and R6 is independently xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OH, xe2x80x94OR7, xe2x80x94OCOR7, xe2x80x94SR7, xe2x80x94N(R7)2, xe2x80x94CN, xe2x80x94CO2R7, xe2x80x94CON(R7)2, or xe2x80x94COR7; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; C4-C7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C1-C4 alkyl where the substituted phenyl or phenyl substituted C1-C4 alkyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, xe2x80x94NR10, xe2x80x94OR10, xe2x80x94COR10, xe2x80x94CO2R10, or xe2x80x94CON(R10)2;
where each R7 is independently xe2x80x94H; xe2x80x94N(R10)2, xe2x80x94NR10COR10, xe2x80x94(CH2)nOR10, xe2x80x94SOnR10, xe2x80x94SOnN(R10)2, xe2x80x94(CH2)nN(R10)2, or xe2x80x94(CH2)nNR10COR10; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; phenyl, substituted phenyl or phenyl substituted C1-C4 alkyl where the substituted phenyl or phenyl substituted C1-C4 alkyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, xe2x80x94NR10, xe2x80x94OR10, xe2x80x94COR10, xe2x80x94CO2R10, or xe2x80x94CON(R10)2;
where each n is independently an integer from 1 to 4;
where each R8 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; phenyl, substituted phenyl or phenyl substituted C1-C4 alkyl where the substituted phenyl or phenyl substituted C1-C4 alkyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, xe2x80x94NR10, xe2x80x94OR10, xe2x80x94COR10, xe2x80x94CO2R10, or xe2x80x94CON(R10)2;
where R9 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl; C4-C7 heterocycloalkyl or heteroaryl; phenyl, substituted phenyl or phenyl substituted C1-C4 alkyl where the substituted phenyl or phenyl substituted C1-C4 alkyl is substituted with xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, xe2x80x94NR10, xe2x80x94OR10, xe2x80x94COR10, xe2x80x94CO2R10, or xe2x80x94CON(R10)2;
where each R10 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; and
where X is independently CH2, O, NH or S; or a pharmaceutically acceptable salt thereof.
Note that when R9 is H, the H undergoes exchange between the adjacent amine and imidazole nitrogen atoms, in a phenomenon called xe2x80x9ctautomerization.xe2x80x9d Throughout this application, the pictorial representation of this structure where R9 is H places the exchangeable H on the amine nitrogen atom.
In a preferred embodiment, the compounds may have the structure: 
where R1, R2, R3, R4, R5, and R6 are as defined above.
In preferred embodiments, the invention includes compounds having the structures: 